The applicability of NMR methods for structure determination of proteins larger than 15 kD is being investigated. Approaches different from those applied to small proteins are needed to decrease spectral crowding associated with the increased number of hydrogens in the molecule. lt has been demonstrated that perdeuteration of all non-exchangeable protons in the protein Staphylococcal Nuclease (18 kD) results in a large improvement of spectral quality of the exchangeable amide protons, permitting identification of the three alpha helical regions. Unambiguous site specific resonance assignments of the amide protons were then obtained by using a novel 13C1-15N double labeling approach. An efficient method has been developed for measuring 1H-1H J couplings in macromolecules where these couplings normally are not directly observable. The method has been applied to the DNA dodecamer d(CGCGAATTCGCG)2. Analysis of the measured couplings indicates that all deoxyribose sugars must undergo rapid conformational transitions between a minimum of two different geometries, a N-type and an S-type conformer. The fraction of time any deoxyribose exists in each conformation varies with its position in the dodecamer with, on average, the pyrimidine nucleotides having more N-character (10-20%) than the purines (0- 10%).